Cutaneous leishmaniasis is a disease characterized by ulcerating skin lesions that are normally self- healing. However some patients develop more severe disease that fails to resolve. While parasite control by the immune response has been well studied, the mechanisms of how lesions resolve, or in some cases fail to resolve, is not well understood. Interestingly, it has been suggested that a pro-inflammatory immune response, rather than an uncontrolled parasite load, plays a large role in the pathology associated with non-healing lesions. We have demonstrated that IL-17 plays a previously unappreciated role in mediating pathology in chronic lesions. These findings prompted us to question what other unknown cytokines could have a role in lesion pathology during Leishmania major (L. major) infections. IL-22, also produced by Th17 cells, has been shown to contribute to the wound healing process through maintenance of the epithelial barrier. However, this cytokine has also been implicated in the progression of other pro-inflammatory skin diseases, like psoriasis. This pathologic role of IL-22 can be influenced by the presence of other pro-inflammatory cytokines. We hypothesize that IL-22 could have dual roles in lesion resolution. In a normal healing model of infection, we hypothesize that IL-22 limits pathology and assists in lesion resolution. However, in a highly inflammatory and non-healing infection, IL-22 exercises its pathologic roles through promoting inflammation. The aims of this proposal will 1) investigate the kinetics of production as well as the sources and targets of IL-22 during healing and non-healing L. major infections and 2) examine how IL-22 limits pathology during healing infections and determine if IL-22 contributes to pathology during non-healing infections. We hope to better understand if augmenting IL-22 could improve treatment of chronic cutaneous leishmaniasis. However, suggesting IL-22 as a potential therapeutic requires the complete understanding of how this cytokine functions in a spectrum of manifestations. We believe that addressing the questions in this proposal will provide us with that knowledge.